How neuronal processes develop and establish proper wiring with their synaptic partners is one of the fundamental questions of neuroscience. The vertebrate retina is an outstanding model system for studying dendritic development and neuronal connections. One of critical visual function, color discrimination, requires precise wiring of retinal neurons. In the mouse retina, there are two types of cone photoreceptors: short wavelength sensitive cones (S-cones), which only express S-opsin, and long wavelength sensitive cones (M-cones), many of which co-express S-opsin. In order to generate color opponency, signals from these two types of cones must be segregated before they are contrasted at the ganglion cell level. True S-cones account for only 2-5% of the total cone population. Thus, downstream S-cone bipolar cells (SCBCs) face the daunting task of seeking out very sparse S-cones from a majority of M-cones. Consequently, SCBCs develop a very unique dendritic arbor with long, meager dendrites that contact few S-cones. This distinctive connection between S-cones and SCBCs makes it an excellent model system to study how presynaptic neurons affect the dendritic development and synaptic targeting of postsynaptic neurons. SCBCs are labeled in a transgenic mouse line expressing Clomeleon (Clm) driven by thy1 promoter. Two mouse models were used to change the density and type of cones. In Thrb2-/- mice which lack thyroid hormone receptor 2 (TR2), M-opsin expression is abolished and all M-cones are turned into S-cones. In S-opsin-/- mice, the S-opsin gene is knocked out. By crossing these two lines, we generated a double knockout (DKO) with neither S- nor M-opsin expression. We found that the numbers of SCBCs in Thrb2-/-, S-opsin-/- and DKO mice are similar to those in wildtype. Morphologically, SCBCs in Thrb2-/- and S-opsin-/- mice were indistinguishable from those in wildtype in terms of number of dendritic branches and cone contacts. SCBCs in these mice appear to specifically target true S-cones, even though the type of opsin expression is identical across all cones. Our results suggest that 1) dendritic development of SCBCs appears to be intrinsic; and 2) S-cone identity may be specified by factors other than S-opsin expressiona hypothesis that we will investigate in the future. In order to compare the transcriptome of S- and M-cones, we need to isolate true S-cones. An existing transgenic mouse line that expresses EGFP driven by an S-opsin promoter was deemed unreliable, because some S-opsin negative cones also express GFP. This is likely due to the short S-opsin promoter region used in generating the mouse line. Due to the low percentage of true S-cones, this contamination from M-cones will be ruinous for RNAseq. In the past year, we have generated a mouse line using the Bacterial Artificial Chromosome (BAC) recombination approach to include longer upstream and downstream regulatory sequences at the endogenous S-opsin gene locus. We successfully screened several mouse lines that express yellow fluorescent protein YFP (Venus) only in S-opsin expressing cones. We are currently working with cell sorting methods to acquire true S-cones from the dorsal retina and to prepare samples for gene profiling experiments. We will compare RNAseq data from S-cones and M-cones and identify candidate genes for their synaptic targeting.